Corticotroph Adenomas

 Corticotroph adenomas arise from T pit pituitary cell lineage and express ACTH and other POMC- derived peptides. They are classified into three subtypes: densely granulated corticotroph adenomas, sparsely granulated corticotroph adenomas, and Crooke cell adenomas. Corticotroph adenomas may also be clinically silent.

Densely granulated corticotroph adenomas account for 10– 12% of surgically removed adenomas and are responsible for Cushing’s disease. These tumours exhibit a marked female preponderance. The age- related occurrence of corticotroph adenomas is similar in both sexes peaking in the fourth decade. Most corticotroph lesions are small microadenomas causing florid Cushing’s disease. The tumours, often measuring only a few millimetres in diameter, may be too small to be conclusively detected by imaging or to be identified at surgery. Therefore, serial sectioning of the biopsied tissue fragments is often needed, which may not always result in the demonstration of the tumour. Histologically, corticotroph adenomas are basophilic and PAS- positive with a sinusoidal or diffuse pattern. Immunoreactivity can be demonstrated not only for ACTH, but for β- endorphin, β- LPH, and CLIP as well. Perinuclear bundles of cytokeratin filaments, characteristic for the human corticotrophs are demonstrated with Cam5.2 as cytoplasmic, peri nuclear pattern.

In a minority of cases, pituitary- dependent Cushing’s disease is brought about by larger tumours. These neoplasms are often as sociated with a milder form of hypercortisolism, but the tumours grow aggressively, often invade, and are frequently macroadenomas at the time of diagnosis. Histologically they exhibit variable, often weak PAS positivity and immunoreactivity for ACTH. A few cases of aggressive macroadenomas also display immunoreactivity for LH and α- subunit. Morphological features of corticotroph adenomas in cases of Nelson’s syndrome are similar to those of densely granulated corticotroph adenomas in Cushing’s disease with few or no cytokeratin filaments.

Sparsely granulated corticotroph adenomas are composed of faintly basophilic or chromophobic cells. They are PAS- positive with patchy immunopositivity for ACTH.

Crooke hyalinization (i.e. excessive accumulation of cytokeratin filaments) is the ubiquitous response of the normal human ACTH cells to the long- lasting elevation of circulating glucocorticoid levels. Accumulation of these cytokeratin filaments causes a glassy hyaline appearance to the cytoplasm and displacement of PAS and ACTH- positive granules to the cell periphery. These ‘Crooke cells’ can be identified using Cam5.2 immunostaining, which displays a strong ring- like pattern around the nucleus. In cases of Cushing’s disease with persistent hypercortisolism after surgery, no evidence of a corticotroph adenoma at pathology, and only pituitary gland obtained, analysis for the presence of Crooke cells is pertinent. Presence of Crooke cells confirms the previous hypercortisolism and will dictate the next step of treatment. Accordingly, Crooke hyalinization would be noted in (1) non- tumorous corticotrophs adjacent to corticotroph adenomas; (2) in ectopic ACTH/ corticotrophin- releasing hormone (CRH) syndrome; (3) in patients with glucocorticoid secreting adrenocortical tumours; (4) and subjects taking glucocorticoids (factitious Cushing syndrome). In cases of pseudo- Cushing, Crooke cells will not be present in the pituitary tissue.

Crooke cell adenomas are a rare type of pituitary tumours. T hey produce ACTH causing Cushing’s disease or may be endocrinologically silent. Crooke hyalinization is not expected to develop in corticotroph tumours yet, a minority of such adenomas contain a variable percentage of adenoma cells displaying this alteration, identical to the Crooke cells seen in the adenohypophysis of patients with glucocorticoid excess. If this change affects more than 50% of the cells, tumours are diagnosed as Crooke cell adenomas. The reason for which Crooke cell adenomas produce ACTH while simultaneously displaying Crooke hyaline changes in response to increased glucocorticoid excess is not well under stood. These tumours are usually invasive, may exhibit aggressive clinical behaviour, and often recur with a low success of cure after reoperation and radiotherapy. Due to their rarity, they present considerable difficulties in assessing prognosis, treatment, and clinical management.

Silent corticotroph adenomas are unassociated with functional activity and present as clinically non- functional tumours. T here are two subtypes of silent corticotroph adenomas. Silent corticotroph adenomas subtype 1— densely granulated— show less female preponderance and different age- related occurrence than corticotroph adenomas associated with Cushing’s disease. The tumours display a high propensity for haemorrhage and may present with pituitary apoplexy. Morphologically the adenomas have the same basophilia, PAS positivity, ACTH and β- endorphin immunoreactivity and ultrastructural features as corticotroph tumours associated with Cushing’s disease. Silent corticotroph adenomas subtype 2— sparsely granulated— have a frequency of 1.5– 2.0% and show marked male preponderance. The tumours appear as non- functioning masses and are usually diagnosed at the macroadenoma stage. Histology reveals chromophobic tumours comprised of small cells, which exhibit only modest PAS positivity and scattered immunoreactivity for ACTH and β- endorphins. No cytokeratin filaments are present with Cam5.2. They can present with aggressive clinical behaviour. These two adenoma types are possibly derived from cells of the pars intermedia.

Molecular Pathology of the T pit Family of tumours

In approximately 40–60% of corticotroph adenomas, somatic mutations in Ubiquitin Specific Peptidase 8 gene (USP8)—resulting in increased EGFR expression and increased mRNA levels of POMC— have been demonstrated. Corticotroph adenomas with mutated USP8 are commonly found in females, present as small tumours with high ACTH production, and are associated with better prognosis. USP8 mutations have not been confirmed in silent corticotroph tumours. Epigenetic mutations in TP53 are linked to corticotroph adenomas.

MicroRNA (miRNA) studies revealed a large number of miRNAs that are upregulated and downregulated. Among those, it was shown that miR- 26a plays a crucial role in cell cycle control of corticotroph adenomas.

Pituitary blastoma, in DICER1 syndrome, is a rare develop mental early childhood invasive neoplasm arising within the fetal adenohypophysis causing infantile- onset Cushing disease. It con sists of a combination of Rathke- type epithelial rosettes, small primitive appearing cells, and secretory cells expressing ACTH. Genetic analysis has revealed a germline DICER1 mutation which is often accompanied by a somatic mutation affecting the RNase IIIb domain of DICER1 in the cases studied.

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مواضيع ذات صلة

Pit- 1 Family of tumours

Pituitary Adenomas

Molecular Mechanisms of Carcinogenesis

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Application of Liquid Biopsy to Non-small- Cell Lung Cancer Lung

Circulating Tumor DNA

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Clinical Development of Venetoclax for Acute Myeloid Leukemia

Clinical Development of Oblimersen for Acute Myeloid Leukemia

Modalities for treating cancer

Tumor markers